Sex-specific fetal lung development and müllerian inhibiting substance.
Male neonates develop respiratory distress syndrome (RDS) with a greater incidence and mortality than do female neonates; the cause of this male disadvantage remains obscure. Male fetuses are exposed to higher levels of androgens and Müllerian inhibiting substance (MIS). Androgens have been shown to inhibit fetal lung maturation, and recent evidence in vitro indicates that MIS, a Sertoli cell-derived glycoprotein made early in ontogeny of the testis, may also inhibit lung development. To study whether this fetal regressor might inhibit maturation of the fetal lung in vivo, we injected human recombinant MIS (rMIS) into fetal rats, measured serum levels of rMIS using an enzyme-linked immunosorbent assay, and analyzed fetal lung tissue histologically and for protein, glycogen, DNA, and disaturated phosphatidylcholine content. Peak serum levels of recombinant MIS were measured at 6 h, with an apparent elimination half-life of 3 h, and without leakage into adjacent littermates injected with vehicle alone. Female fetal rat lung tissue exposed to recombinant MIS (10(-9) M, 10(-8) M) revealed depressed disaturated phosphatidylcholine content both 48 and 72 h after injection compared with female vehicle-injected littermates. Male lungs of the same gestational age appeared inhibited at a higher (10(-8) M) rMIS dose. These inhibitory effects observed in vivo confirm those previously seen in vitro and suggest that MIS, as well as androgens, may play a causative or important ancillary role in the sexual dimorphism that characterizes the neonatal respiratory distress syndrome.
Catlin
E A
EA
Pediatric Surgical Research Laboratory, Massachusetts General Hospital, Boston 02114.
Powell
S M
SM
Manganaro
T F
TF
Hudson
P L
PL
Ragin
R C
RC
Epstein
J
J
Donahoe
P K
PK
D000818:Animals; D054304:Anti-Mullerian Hormone; D003864:Depression, Chemical; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005312:Fetal Blood / Q000032:analysis; D005325:Fetal Organ Maturity / Q000187:drug effects; D006023:Glycoproteins; D006131:Growth Inhibitors / Q000097:blood / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000196:embryology*; D008297:Male; D009095:Mullerian Ducts / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins / Q000097:blood / Q000302:isolation & purification / Q000494:pharmacology; D012727:Sex Characteristics; D013735:Testicular Hormones / Q000097:blood / Q000302:isolation & purification / Q000494:pharmacology*; D013997:Time Factors
D006023:Glycoproteins; D006131:Growth Inhibitors; D011994:Recombinant Proteins; D013735:Testicular Hormones; D054304:Anti-Mullerian Hormone